Phytotherapeutic mechanism of medicinal plants with wound-healing potential: a mini-review

The applications of medicinal plant species for diverse therapeutic effects are well documented throughout the world. In recent times, the screening of higher plants for unique biologically active compounds, particularly those with pronounced therapeutic potency, has received the interest of the science community. A wound is a loss or breaks in the anatomic stability of active tissue. It not only poses a physical and mental threat to zillions of people but could cause the failure of multiple organs, amputation, and even death. Therefore, thousands of plants have been screened to obtain active metabolites or compounds that can accelerate the process of restoring the damaged tissue structure and inhibit the probability of infections. Due to the severity of wounds to the human body, it is essential to explore safe, economical, and environmentally friendly therapeutics from nature. This review aims to conduct a comprehensive search of medicinal herbs to uncover their therapeutic potential, identify gaping holes, and assess future research prospects that could lead to the discovery of novel pharmacophores. Thus, the review is tailored towards the appraisals of phytotherapeutic mechanism and wound healing efficacy of medicinal plants, which will help spur future research and improve our current knowledge leading to the unearthing of novel and potent pharmacophores with pronounced wound healing potentials. Several medicinal plants with scientifically proven wound-healing activities are reported and discussed alongside phytochemicals present their various extracts and isolates. The achievable wound-healing closure rate of each plant was also reported with a focus on what is responsible for the healing rate.


Introduction
Wounds refer to the anatomical or physical disruptions caused by tearing, breaking, piercing, or cutting the skin epithelium and could be associated with connective tissue loss (Lordani et al., 2018). It represents an important global healthcare challenge due to the high cost and inept therapeutic agents in managing wounds (Agyare et al., 2016). In recent times, the impulse to search or explore potent wound therapeutics by researchers is voracious.
Most of these researches are tailored towards unearthing innovative pharmacophores with the primary target of enhancing wound healing and also eradicating aftermath consequences. Traditional medicine has received longstanding interest since time immemorial as the major healthcare delivery system, especially in developing countries (Pei, 2001;Edewor et al., 2015). It is also documented as the foremost medical care is known and is gaining more ground in both emerging and industrialized countries because it is safe, cost-effective, and eco-friendly, coupled with no side effects (Oladeji et al., 2020a). The exploit of herbal drugs in primary health care is considered the oldest therapeutic system since the inception of man. According to the World Health Organization (WHO), herbal medicine is an alternative pathway in combating diseases and infections (WHO, 2016). Herbs are therapeutic constituents obtained from nature to treat various acute and chronic diseases (Kayser et al., 2003).
The scientific approach has piloted the discovery of chemotherapeutic substances which have effectively inhibited plasmodium development, targeting the parasites at the blood stage of their life cycle. Several pharmacophores such as quinine (QN) were discovered in the nineteenth century and showed strong inhibitory activities against plasmodium species. However, at the arrival of synthesized drugs, plants and plant parts are used as drugs contracted. Unfortunately, as the use of synthesized drugs amplified, there was also an upsurge in resistance to the synthesized drugs by microbes, joined with the lethal nature of the drugs. Moreover, individuals respond to some of these drugs in different ways. These drawbacks of synthesized drugs triggered man to turn back to his genesis drugs source (plants) for his primary healthcare delivery, and this has brought about the use of an enormous number of medicinal plants with curative properties to treat several diseases (Oladeji et al., 2021;Edewor et al.,2015). The therapeutic actions of plants have been ascribed majorly to the secondary metabolites present in them (Fabeku, 2006). In addition, phytomedicine has shown outstanding potential in managing contagious ailments (Yesilada, 2005). Therefore, great attention has been given to the uses of plants and plant products, especially in those regions with no or slight access to new health facilities (Pei, 2001). Traditional healers were compelled to use any natural substance to ease their pains, instigated by acute and chronic ailments, physical discomforts and wounds, and deadly infections (Yesilada, 2005).
However, the present phytochemical research is insufficient to support the use of plants as possible wound healers.
As a result, this review is geared toward conducting a comprehensive search of medicinal herbs to uncover their therapeutic potential, identify gaping holes, and assess future research prospects that could lead to discovering novel pharmacophores.

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Wounds and wound healing mechanism
The wound does not only affects the physical and psychological well-being of zillions of patients but also inflict a substantial cost on them, and recent evaluations show that about 6 million people are suffering from chronic wounds, which may even lead to failure of multiple organs and even death (Kumar et al., 2007). According to the Wound Healing Society, Wounds are physical injuries that result in an opening or fracturing of the skin, interrupting normal skin biomechanical operation and possibly resulting in epithelium loss with or without impairment to the core connective tissue (Strodtbeck, 2001). The healing of a wound is a continuous process of three uninterrupted and over-lapping stages encompassing restoring normal structure and functions of damaged tissue or a survival mechanism that characterizes an attempt to maintain the normal anatomical structure (Lenselink 2015;Puratchikody et al., 2006). Though wound healing is an acquainted process, its fundamental biology is complex and moderately stopped because unhealed wounds frequently develop inflammatory intermediaries that bring forth soreness and puffiness at the wound location (Sherratt and Dallon, 2002;Roberts et al., 1998).

Classes of wounds
Wounds are classified as closed or open wounds depending on the underlying source of wound genesis and as acute or chronic wounds based on wound healing physiology (Matadeen et al., 2014;Yogesh et al., 2013;Shivani et al., 2012).

Open wounds and closed wounds
Open wounds cause blood to flow out from the body alongside noticeable hemorrhage. In contrast, a closed wound causes blood to flow out of the circulatory system but lingers in the body, resulting in confusion. (Table 1).

Acute wounds
Acute wounds are described as tissue injuries treated in a systematic and timely manner, resulting in the restoration of anatomical and functional integrity. Cuts are the most common cause of acute wounds, and the repairing phase is typically completed within a reasonable time frame (Yogesh et al., 2013;Shivani et al., 2012).

Chronic wounds
Chronic wounds do not heal normally and cause pathologic discomfort as a result. Chronic wounds are the chief root of physical disability and either take a long time to repair, don't heal, or return regularly (Menke et al., 2007).
A clean and uninfected surgical incisional wound approximated by surgical sutures is an example of a chronic wound (Yogesh et al., 2013;Shivani et al., 2012;Menke et al., 2007;Jie et al., 2007). Ablation, antibiotics, tissue implantations, and proteolytic enzymes are some of the latest methods for treating chronic wounds. However, they all have downsides and severe side effects (Chitra et al., 2009).

Mechanism of Wound Healing
Wound healing can be defined as a complex process, with the wound environment fluctuating with the shifting health status of a person (Heather et al., 2011). In a normal phenomenon, the outmost and the innermost layer of the skin occurs in steady-state equilibrium. It forms a shielding wall contrary to the external environment, which instantaneously instigates the usual pathophysiological mechanism of wound healing when broken due to injury.
When the skin is injured, complex biochemical reactions occur in a well-ordered sequence to repair the damage.
Platelets clump together at the injury site to produce a fibrin clot a few seconds just after the injury. This clot helps to control aggressive bleeding and achieve haemostasis. This all-encompassing healing process, which begins as soon as an injury occurs, might linger for the donkey months or years (Lazarus et al., 1994). Figure 1. Described the uninterrupted, overlapping, and precisely programmed three phases of the wound healing process: inflammation, proliferation, and tissue remodeling (Shivananda et al., 2009;Jie et al., 2007).

 Inflammatory phase: This phase begins instantly after the wound and generally lasts for about 24 and 48
hours and may continue for about two weeks. The inflammatory stage unveils the haemostatic systems that instantaneously stop blood loss at the wound site (Yogesh et al., 2013;Jie et al., 2007). This hemostasis mechanism is the first step in the inflammatory phase. It consists of two major processes: developing a fibrin clot and coagulation (Jie et al., 2007), which commences straightaway after wounding, with vascular constriction and fibrin clot creation. Then, proinflammatory cytokine and growth factors such as transforming growth factor, plateletderived growth factor, fibroblast growth factor, and epidermal growth factor are released by both the clot and the underlying wound tissue (Yolanda et al., 2014;Guo and DiPietro, 2010).  Remodeling phase: This phase continues for about twenty-one days to two years. Fresh collagen is forged at this stage. One of the critical features of the remodeling phase is Extracellular matrix remodeling to an architecture that approaches that of the normal tissue (Jie et al., 2007;Guo and DiPietro, 2010). Type III collagen (which is prevalent during proliferation) becomes gradually degraded and replaced by type I collagen during this phase. And thus, the realignment of collagen tissue takes place, and the intermolecular cross-linking of collagen caused by vitamin C-dependent hydroxylation increases tissue breaking strength (Yolanda et al., 2014;Yogesh et al., 2013).
As a result, the scar smoothness and tissues become 80 percent tougher than the original tissue (Yogesh et al., 2013). According to Guo and DiPietro, 2010, (Guo and DiPietro, 2010).

Roles of phytochemical in wound healing
The healing of a wound as a process is a natural occurrence by which the body overcomes damage to the tissue.
However, the healing pace is slow, and the probability of microbial septicity is very high. This calls for the great request of substance that accelerates the healing process (Sherratt & Dallon, 2002). Phytochemicals are bioactive compounds that occur naturally in plants as secondary metabolites that work with nutrients to protect against pathogenic attack, and research has demonstrated its protective effects against various diseases (Opawale et al., 2017;Altiok, 2010). Some of the biological properties of these secondary metabolites include antioxidant activities, antimicrobial effects, stimulation of the immune system, astringent and anticancer properties (Altiok, 2010).
Though phytochemicals are not vital nutrients and are not necessary by the human body for sustaining life, but have important properties to avert or fight some diseases (Emmanuel et al., 2014). Phytochemicals are classified as tannins, alkaloids, terpenoids, phenolic compounds, flavonoids, glycosides, saponins, anthraquinones, and so on (Altiok, 2010). Figure 2. Summarized the key function of phytoconstituents like triterpenoids, alkaloids, and flavonoids in the process of wound healing because of their astringent and antimicrobial properties, which are thought to contribute to wound closure (contraction) and an increment in epithelialization rate (Emmanuel et al., 2014). Narendhirakannan et al., 2012 also stated that tannins, phenols, and flavonoids could be answerable for healing owing to their antioxidant properties. An increase in total antioxidant status has been essential in recovery from wounds (Narendhirakannan et al., 2012).

Plumbago zeylanica
Plumbago zeylanica belonging to the family Plumbaginaceae has been reported to be employed by the majority of the prehistoric people primarily for wound healing activity, among other issues and the Kodati team in 2011 evaluated the wound healing potential of this plant to further emphasize its pharmacology and phytochemistry.
Their findings reveal that the methanolic root extract of Plumbago zeylanica has remarkable wound healing activity in rats, with a 100 percent wound healing rate compared to the control, which is 80.64 percent. The wound-healing action of methanolic root extracts of Plumbago zeylanica, according to the Kodati research team, could be attributed to the presence of bioactive compound reported in Table 2. (Kodati et al., 2011)

Kigelia africana
Kigelia africana is an excellent medicinal plant employed to alleviate fungal infestations, psoriatic arthritis, dermatitis, and cancer (Agyare et al., 2013). Kigelinone, vernolic acid, kigelin, iridoids, luteolin, and 6hydroxyluteolin have been detected in the root, wood, and leaf of this plant. In comparison to untreated wound tissues, extract-treated wound tissues exhibited better collaboration, re-epithelialization, and fast granulation development. As shown in

Strophanthus hispidus
Strophanthus hispidus belonging to the family Apocynaceae is used as an antidote to poison and to combat skin ailments such as fungal infestations, psoriatic arthritis, dermatitis, and cancer, boils, leprosy, syphilis, as well as cancer (Ayoola et al., 2008;Agyare et al., 2013). Powerful antioxidant and antimicrobial bioactive compounds have been reported to be present in the root, wood, and leaf (Agyare et al., 2013). Extract-treated wound tissues showed improved collagenation, re-epithelialization, and granulation growth compared to untreated wound tissues (Ayoola et al., 2008). As shown in Table 2, from the result of the study carried out by Agyare et al. in 2013, leaves and roots methanolic extract of Strophanthus hispidus was found to contain important phytochemicals which are responsible for the 100% healing rate of the extract when compared with the control which gave 96.59% on the last day of the experiment.

Aspilia africana
Aspilia Africana, a common weed of filed crop in the forest region, is one of the many indigenous plants used in folk medicine to curb certain illnesses such as rheumatic pain, anticoagulating activities, anti-malaria, and so on and was found to contain vital phytochemicals such as Alkaloids (most prominent), Saponins, Flavonoids, Tannins, Phenols (the lowest) as well as vitamins (Abii and Onuoha, 2011;Osunwoke et al., 2014). Furthermore, from the result of the research done by Osunwoke and his coworkers in the year 2013, it was evident that the aqueous extracts of the leave of Aspilia africana promotes wound healing activity through increased inflammatory response and neovascularization with a recovery rate of 82.21%, as compared to the untreated group with 52.84%.

Swietenia macrophylla
Swietenia macrophylla is a well-known medicinal herb. Duravi research team previously reported on the phytochemical screening and antimicrobial activity of leaf, seed, and fruit in 2016. The phytochemical assays indicated the presence of prevalent phytocompounds like alkaloids, flavonoids, tannins, terpenoids, glycosides, saponins, volatile oils, amino acids, and proteins as principal active constituents, and the seed extract had huge anti-proliferative effects on bacterial and fungal replication and growth (Duravi et al., 2016). In 2017, the Kiran research group investigated the tissue regeneration ability of an ethanolic extract of Swietenia macrophylla seeds ointment in an excision wound model using a white rat. In terms of wound contraction ability, wound closure time, and epithelialization period, the extract ointments worked fairly well in the excision wound model as the group treated with conventional medicine Betadine ointment and the control group. The proposal that Swietenia macrophylla seed extract demonstrates considerable wound healing was also supported by histological investigation. Swietenia macrophylla has been discovered to have remarkable wound-healing abilities. This was demonstrated by reducing wound closure and epithelialization time (Kiran et al., 2017).

Azadirachta indica
Azadirachta indica (Neem tree) of Meliaceae family is an evergreen tree that is prevalent in Asia but has now grown in Western Africa region and has been confirmed to contain important phytochemicals such as Alkaloids, wound-healing activities, and its oil has been found to boosts wound tensile strength and wound closure rate, according to (Barua et al., 2010;Maan et al., 2010;Pandey et al.,2012).

Mallotus oppositifolius
Mallotus oppositifolius is called Nyanyafurowa by the Ghananians and Ukpo in Nigeria. Tapeworms and diarrhea have both been medicated with a leaf and stalk peel infusion. To relieve pain, crushed or chewed raw leaf blended with butter is applied to injuries and blisters and rheumatism, dermatitis, and burns sometimes blended with butter.
Decoction of the leaves is used for the management of headaches, epilepsy, or mental illness. The crushed leaves or leaf sap are applied to aching teeth and inflamed eyes (Agyare et al., 2014). In a study conducted by Agyare et al., methanolic leaf extract of Mallotus oppositifolius produced a considerable inflammatory response, fibrosis, and collagenation in an excision wound model (Agyare et al., 2014).

Momordica charantia
Momordica charantia, a member of the Curcubitaceae family, is also famously known as bitter gourd, bitter lemon, and Nyanya in Ghana. The plant has historically been used to heal wounds, ulcerative colitis, malaria, hemorrhoids, dermatitis, parasitic infections, and yaws (Burkill, 2000). In contrast, histological examination of the wound tissues revealed strong fibrosis and collagenation (Agyare et al., 2014).

Tridax procumbens
The plant Tridax procumbens is popularly referred to as "coat buttons." The effects of whole plant extract, aqueous and ethanolic extract of Tridax procumbens on lysyl oxidase activity, protein and nucleic acid contents, and tensile strength, all of which are essential for wound healing, have been documented in the literature, with a large increase in animals treated with aqueous and ethanolic extract fractions compared to the untreated in diverse wound healing simulations (Alankar et al., 2020;Yaduvanshi et al., 2011). Excision wounds treated with extract of the juice of Tridax procumbens (1 mg/g) showed a considerable rise in collagen production of 38.81 percent in comparison to vehicle-treated wounds, according to Yaduvanshi et al., 2011. In cutaneous wounds treated with Tridax procumbens juice extract, histopathological analyses revealed enhanced infiltration of proinflammatory cells, fibroblast proliferation, and re-epithelialization with mild vascularity. Dermal wounds treated with Tridax procumbens juice extract at a dose of 4 mg/g, on the other hand, produced inflammation, oedematous tissue, and impaired vascularity (Alankar et al., 2020;Yaduvanshi et al., 2011)

Crinum jagus
Crinum jagus belonging to Lilliaceae family, is a tender perennial bulb with tulip-like (showy) white flowers and called Bush onions, and it's found in tropical and subtropical areas all over the world .
The study of Udegbunam et al., in 2015 have established that the wound healing of Crinum jagus extract partly increasing collagen deposition and epithelialization, and the extract elicited the best wound healing activity at a concentration of 10%, and the activity was concentration-dependent. They  suggested that the wound healing potentials of the extract could be attributed to the presence of polyphenolic compounds, including tannins, saponins, glycosides, and alkaloids in the extract.

Bridelia ferruginea
Bridelia ferruginea of the genus Bridelia belonging to the family of Euphorbiaceae is a savannah species

Radix paeoniae
Radix paeoniae (Paeonaceae) is used to reduce pain and treat amenorrhea, painful injuries, hemoptysis, inflammation, furuncle, and ulcers (Xing et al., 2004). Excision, incision, and dead space wound models on Wistar rats were used to test aqueous extracts of Radix paeoniae roots for wound healing. In addition, tissue breaking strength, epithelialization, wound contraction, and granulation tissue dry weight were investigated. Compared to the Nitrofurazone ointment-treated control group, the test group showed considerable wound-healing efficiency (Malviya and Jain, 2009).

Hibiscus rosa sinensis
Hibiscus rosa sinensis belonging to Malvaceae family is an indigenous tropical and sub-tropical plant (Kumar and Singh, 2012) that has been used conventionally for the management of a wide range of diseases which includes promotion of wound healing and some other biological activities such as antihypertensive, antitumor, antioxidant, and so on. In rats, ethanolic leaf extract (120 milligrams per kilogram per day) reduced wound area by 86 percent compared to controls (75 percent decrease). Similarly, the extract-treated rats had comparatively stronger skin breaking strength and epithelialization than the controls (Bhaskar and Nithya, 2012). In addition, granulation tissue dry and wet weight and hydroxyproline level were documented to have increased significantly compared with controls. Bhaskar and Nithya used excision, incision, and dead space wound models to investigate the effects of an ethanolic extract of Hibiscus rosa s. flowers on Wistar rat. As indicated by rises in DNA, total protein, and total collagen content of granulation tissues, the extract boosted cell growth and collagen formation at the injury site.
Furthermore, compared to the control, the extract facilitated wound healing drastically, as revealed by better epithelialization and wound contraction rates and higher wound tensile strength, and wet and dry granulation tissue weights (Bhaskar and Nithya, 2012).

Alternanthera sessilis
Alternanthera sessilis belonging to the Amaranthaceae family of plants is historically used to treat ulceration, lesions, wounds, fevers, ophthalmia, gonorrhea, skin rash, burning sensations, dysentery, indigestion, skin liver and spleen ailments (Kannan et al., 2014;Hossain et al., 2014). Previously, the wound-healing activity of Alternanthera sessilis was carried out by Jalalpure et al. 2008. The oral administration of the plant's chloroform leaf extract at a 200 mg/kg body weight dose resulted in a vastly reduced wound area and improved re-epithelialization in rats.
Meanwhile, the scar size following full epithelialization was revealed to be 33.2±0.7 mm 2 in the excision wound model, with wound breaking strength of 388±5.85 gram in the incision wound model, and granuloma dry weight of 47.7±2.29 gram and granuloma breaking strength of 247±10.2 gram in granuloma analyses (Jalalpure et al. 2008).  Kannan et al., 2014;Hossain et al., 2014;Jalalpure et al. 2008 HWC: Highest wound closure in percent; HSBS: Highest skin breaking strength in gram

Recent development on the use of plants for medicinal purpose
In recent times, researchers have focused more on combining the strength of modern days' scientific techniques such as FTIR, GS-MS, and NMR to identify the key architects of phytoconstituents.
Also, other minor metabolites are being harnessed by researchers in recent times to further campaign the importance of medicinal plants in the health care system. Furthermore, agreement between oral and topical use of the medicinal plant has gained the full interest of many chemists nowadays to further understand the chief working mechanism of medicinal plant in the body.

Future work and research direction
It is glaring that artificial intelligence (AI), including machine learning and deep learning, has not been fully deployed into computer-aided drug design (CADD) and bioactive compound identification in the plant extract.
Thus, effort must be channeled in this direction.
A variation in the chemo-taxonomical balance of the phytochemicals in the plant as caused by changes in the environment could pose an inherent enervating danger to honorable consumerists of the plant extracts. Hence, maiden biosafety tests should be done before the administration of the plant extracts for therapeutic purposes and find a way to safeguard biodiversity to prevent the prominent plants of medicinal value from being defunct. In addition, a well-designed clinical evaluation needs to be worked upon. Serious work should be done on the LD 50 dose-response concentration that might cause side effects like epidermal degeneration. Researchers could probe the isolated bioactive compound responsible for the wound-healing activity separately to develop wound healing drugs with sound therapeutic value. Also, trial research should be done in combining/extracting two or more medicinal plants together to treat wounds because this will increase the probability of having all the key phytochemicals responsible for wound healing in a reasonable quantity in one formulation.

Conclusion
A mini-review of the wound-healing potential of medicinal plants has been carried out in this study. Wound healing is a biochemical process that starts with damage and ends with the creation of scar tissue. The chief aim of wound management is to prevent susceptibility factors that inhibit wound healing (for example, poor diet, infection at the wound site, diabetes), enhance the healing process, and reduce the incidence of wound contagions. This review has shown that medicinal plant plays a chief role in meeting the unbeatable goals of wound management, and thus, cannot be overlooked at any point in time no matter how. Over the years, medicinal plants have been used in folk medicine as topical and oral preparations to know the roles of phytochemicals in wound healing to promote wound care and healing activities. This review also suggested that these plants possibly owe their wound healing processes to the antimicrobial, astringent, anti-inflammatory, and antioxidant properties combined with the various phytochemicals present. Also, from this review, we can conclude that the most widely used method of application of extract formulation is topical. In most cases, only the wound closure rate is commonly and frequently assessed, unlike the skin breaking strength after or during the healing period.

Declaration of Conflict of Interests
The authors declare no conflict of interests.

Funding
No source of funding for the work